Phenothiazine compositions and method of treating mental disorders



United States Patent 3,194,733 PHENGTIHAZINE CUMEQSHTIGNS AND METHQD 0FTREATKNG MENTAL DISORDERS Harry L. Yale, New Brunswick, and Reynold C.Merrill,

Short Hills, N.J,, assignors to Qiin Mathieson Chemical Corporation, NewYork, N.Y., a corporation of Virginia No Drawing. Filed Jan. 28, 1963,Ser. No. 254,459

11 Claims. (Cl. 167-65) This invention relates to new acid esters ofphenothiazines having valuable therapeutic properties, pharmaceuticalcompositions containing the same, and processes for the preparationthere.

This application is a continuation-inpart of a previous applicationSerial No. 105,548, filed April 26, 1961, now abandoned.

The therapeutically active compounds of this invention includephenothiazines of the general Formula I wherein n is a positive integerof more than 6 and is preferably a positive integer of from 7 to 12. Theterm ary as employed herein includes substituents derived frommonocyclic and bicyclic aryl carboxylic acids, and may be substituted orunsubstituted and further may be represented by the formulae whereineach R may be hydrogen, lower alkyl, lower alkoxy or halogen (e.g.chloro or brorno) and R is preferably hydrogen, lower alkyl or loweralkoxy, and most preferably, R is hydrogen or lower alkyl. Examples ofthe aryl carboxylic acids which may be employed include benzoic,o-toluic, 2,6-dimethylbenzoic, 2,6-dimethylanisic, o-bromobenzoic,o-chlorobenzoic, 2,6-dichlorobenzoic, naphthoic acid, dimethylnapthoicacid and other like acids.

The preferred compounds of this invention are those wherein X is chloroor trifluorornethyl and Y is a higher alkyl, higher alkenyl or higheralkynyl radical of from six to fourteen carbon atoms, lower alkylorlower alkoXy-substituted aryl or w-carboalkoX3 (higl1er alkyl) of lessthan 13 carbon atoms. Particularly preferred are those compounds whereinX trifiuoromethyl and Y is a higher alkyl radical of from nine tofourteen carbon atoms.

Since the compounds of this invention are especially adapted forparenteral administration, as more fully discussed hereinafter, they arepreferably administered in the form of their free esters.

The compounds of this invention are therapeutically active substanceswhich are utilizable as tranquilizing (or ataractic) agents. Thesecompounds differ from the corresponding lower alkanoic acid esterderivatives or the free hydroxyl derivatives in that they aresignificantly longer acting when administered parenterally and thus,when injected subcutaneously, for example, in a suitable vehicle, yielda long acting tranquilizing drug.

The compounds of this invention can be prepared by interacting acompound of the general Formula II wherein X and r are as hereinbeforedefined, with an acyl halide (preferably acyl chloride) of the formula:YCO-halide, wherein Y is as hereinbefore defined; the reactionpreferably being conducted in an organic solvent, such as chloroform,for the reactants. Among the suitable phenothiazine reactants may bementioned: 10 [3-(Z-hydroxyethyl)piperazinopropyl]phenothiazine; l0[3-(Z-hydroxyethyl)piperazinopropyl]-2-halo-pheno thiazines, such as10-[3-(2-hydroxyethyl)piperazinopropyl] -2-chlorophenothiazine; 10-[3(Z-hydroxyethyl) piperazinopropyl] 2 trifiuoromethylphenothiazine;10-[3-(2= hydroxyalkoxyalkyl)-piperazinopropyl] 2-halo-phenothi azines,such as l0-[3-(2-hydroxyethoxyethyl)piperazinopropyl]2-trifiuoromethylphenothiazine; 10[ 3 (2 hydroxyethyl)piperazinopropyl]2-(lower alkyl)phenothiazines, such as10[-3-(2-hydroxyethyl)piperazinopropyl]- Z-methylphenothiazine; 10[-3(2-hydroxyethyl(piperazinopropyl1-2-(lower alkoxy)phenothiazines, suchas 10- [-3-(Z-hydroxyethyl)piperazinopropyl1- Z-methoxyphenothiazine; 1O[3 (2 hydroxyethyl)piperazinopropyl] -2- (lower alkanoyl)phenothiazines,such as 10-[3-(2-hydroxyetliyl)piperaziuopropyl]2-propionylphenothiazine; 10-[3-(2-hydroxyethyl)piperazinopropyl]2-(lower alkyl mercapto) phenothiazines, such as 10[-3-(2-hydroxyethylpiperazinopropyl] Z-methylmercaptophenothiazine; 10- [3 (Z-hydroxyethylpiperazinopropyl] -2-trifluoromethylmercaptophenothiazine and10-[(2-hydroxyethyl)piperazinopropyl] -2-methylsulfonylphenothiazine.

Among the suitable acyl halide reactants may be mentioned the acylchlorides of higher alkanoic acids, such as heptanoic acid, octanoicacid, Z-ethylheptanoic acid, 2,2-diethylbutyric acid, capric acid,lauric acid, tridecyclic acid, myristic acid, palmitic acid, and stearicacid; the acyl chlorides of higher alkenoic acids, such as 2-heptenoicacid, 2-nonenoic acid, citronellic acid, undecylenie acid and oleicacid; the acyl chlorides of the alkynoic acids, such as heptynoic acid,octynoic acid, nonynoic acid, decynoic acid, dodecynoic acid,tri-decynoic acid and octadecynoic acid; the acyl chlorides of thealkadienoic aids, such as heptadienoic acid, octadienoic acid,(alkyl)-octa dienoic acid (e.g., 7-methyl-octadien-oic acid), andnonadienoic acid; the acyl chlorides of the carboalkoxyalkanoic acids,such as carbomethoxyoctanoic acid, carbomethoxydecanoic acid andcarbomethoxyundecanoic acid; the acyl chlorides of aryl carboxylicacids, such as benzoic acid, o-toluic acid, dirnethylbenzoic acid,dimethylanisic acid, o-bromobenzoic acid, o-chlorobenzoic acid, napthoicacid, dimethylnaphthoic acid, benzilic acid and dichloroas benzoic acid;the acyl chlorides of the carboalkoxy alkenoic acids such asw-carbomethoxyundecylenic acid, (.0- carbomethoxydodecylenic acid; andthe acyl chlorides of the carboalkoxyalkynoic acids, such asw-carbomethoxyundecylynic acid, w-carbomethoxydodecylynic acid, andother like acids.

All of the acyl halides described hereinbefore may be prepared byheating an acid of the formula Y-COOH, wherein Y is as hereinbeforedefined with two parts by Weight, of a thionyl halide, preferablythionyl chloride or thionyl bromide, alone, or in the presence of ananhydrous solvent, such as chloroform or benzene, under reflux for aperiod of about three hours, concentrating to remove the excess thionylhalide (and any solvent present), and then distilling to obtain theresultant acyl halide, YC-halide, wherein Y is as hereinbefore defined.

In addition to the foregoing general procedure, to prepare compounds ofFormula I, an alternate procedure may be employed. In this alternateprocedure, compounds of Formula II are employed as starting materials,which starting materials are first reacted with a halogenating agent,such as thionyl chloride or thionyl bromide, to yield compounds ofgeneral Formulae III.

s (III) wherein X is as hereinbefore defined and B is halogen, which arealso new compounds of this invention.

The compounds of Formula 111 are then reacted with. a suitable alkalimetal salt of the carboxylic acids of the formula Ii Y- (Q) wherein Q isan alkaline metal (cg, Na, K, etc.) and Y is as hereinbefore defined toyield respectively the new final products of Formula I.

A further alternate procedure for obtaining the compounds of thisinvention involves the reaction of the compound of the Formula IV.

II Halogen-(011 C H O) C-Y wherein Y and r are as hereinbefore defined.

Another alternate suitable method of preparing the compounds of thisinvention involves the reaction of a 4, compound of Formula II with acompound having the formula i Y (LJ 0 (alltyl) wherein Y is ashereinbefore defined, in the presence of a trace amount of sodiummethoxide catalyst, to yield compounds of Formula I. l

The compounds of the formula may be prepared by esterifying a suitableacid of the formula Y COOH, wherein Y is as hereinbefore defined, with alower alkanol, e.g., methanol or ethanol, in the presence of an acidiccatalyst, e.g., sulfuric or hydrochloric acid, or with an alkylatingagent, such as diazomethane or diazoethane, to yield compounds of theformula Y-i O (alkyl) wherein Y is as hereinbefore defined.

To prepare the preferred compositions ofthis invention, the compoundsofthis invention, in the form of their free basic esters, are dissolvedor suspended in a parenterally acceptable liquid vehicle. For prolongedaction, the compounds are formulated in an oil such as peanut oil,sesame oil, cottonseed oil, corn oil, soybean oil, synthetic glycerolesters of long chain fatty acids, and mixtures of these and other oils;the compound preferably being present in a concentration to give about20 mg. to about 300 mg. or" the compound per n11. The preferable routeof administration of these formulations is subcutaneous.

The following. examples illustrate the invention (all temperatures beingin centigradc):

Example 1.Acid chloride of heptafnoic chloride 30 gm. of heptanoic acidand 60 gm. of thionyl chloride are mixed, kept at room temperature forone hour, refluxed for three hours, concentrated until free of thionylchloride and the residue distilled to give the acid chloride ofheptanoic acid.

Similarly, following the procedure set forth in Example 1, butsubstituting an equivalent amount of thionyl bromide for thionylchloride there is obtained the acid bromide of heptanoic acid.

Example 2.Heptanoz'c acid ester of 10-[3-(2-hydr0xyethyl)piperzzzinopropyl] -2-zrifluoromethylphenothiazine (2.) Preparation ofthe lzeptzmoic acid ester of 10- [3-(2- lzydroxyethyl)piperazinopropyl]Z-Irifluoromethylphenothiazz'ne, dihydrochloride, hemihydrare.To astirred solution of 30.6 g. of 10-[3-(2-hydroxyethyl)piperazinopropyl]-2-trifiuoromethylphenothiazine in 300 ml. of drychloroform is added, dropwise, 11.9 g. of heptanoyl chloride in 50 ml.of dry chloroform. Subsequen ly, the reaction mixture is stirred andheated under reflux for five hours, cooled, and shaken with 5% aqueoushydrochloric acid. The dried chloroform solution is concentrated toabout 50 ml., cooled and diluted with about 450 ml. of anhydrous ether.To this cooled solution is added about 10 ml. of ethereal hydrogenchloride. The crystalline solid which separates is boiled for about fiveminutes with 200 ml. of benzene. The solid first dissolves and thencrystallizes from boiling mixture. The cooled mixture is filtered, andthe solid recrystallized from methyl ethyl ketone to give about 19.6 g.of the product, M.P. about 184- 185 (dec.).

(b) Preparation of the heptaizoic acid ester of 10-[3- (2lzydroxyethyl)piperazinopropyl] 2 trifluoromethylphen0thiazine.Anice-cooled mixture of the dihydrochloride obtained in step (a), 500 m1.of 5% aqueous potassium carbonate solution and 1080 ml. of other arestirred until all the solid has reacted. The ether layer is sepa- 5rated, dried and concentrated to give about 18.8 g. of prodnet as aviscous pale yellow oil, 11 1.5485.

Similarly, by substituting an equivalent amount of the following acylchlorides for the heptanoyl chloride in step (a) of Example 2, andfollowing the procedure of steps (a) and (b), the indicated ester isobtained:

Acyl chloride Ester Gctanoyl chloride Octanoic Lauroyl chloride LaurieStearoyl chloride Stearic Similarly, following the procedure set forthin Example 1 but substituting an equivalent amount ofl-O[3-(2-hydroxyethoxyethyl)piperazinopropyl] 2trifiuoromethylphenothiazine for 10[3-(Z-hydroxyethyi)piperazinopropyl]-2-trifiuoromethylphenothiazineyields the heptanoic acid ester of10-[3-(Z-hydroxyethoxyethyl)piperazinopr0 pyl]-2-trilluoror1ethylphenothiazine.

Example 3.2,2-dietlzylbutyric acid ester ofl--[3(2-hydroxyctlzyl)pipemzinopropyl] 2 ti'i lzloromethylphenothiazineTo 39.3 g. of lO-[3-(Z-hydroxyethyl)piperazinopropyl}Z-triiluorornethylphenothiazine in one liter of dry chloroform is added,dropwise, 33.8 g. of 2,2-diethylbutyroyl chloride in 100 ml. of drychloroform. The mixture is then refluxed for two hours and concentrateduntil free of chloroform. The residual oil is added to a suspension of40 g. of sodium bicarbonate in 400 ml. of ice water and 5 00 ml. ofether. The mixture is shaken carefully until no further evolution ofcarbon dioxide occurs, the ether layer is separated, dried andconcentrated to give 2,2-diethylbutyric acid ester of1%-[3-(2-hydroxyethyl)piperazinopropyl]-2-trifiuoroniethylphenothiazine, as a pale yellow oil.

Example 4.2,2-dietlzylbtlzyric acid ester 0 -[3-(2-1231-droxyetlzyl)piperazinopropyl] Z-trifluoromethylphenozlziazlnc, salt with2 moles of mal-zic acid 11.6 g. of the product obtained in Example 2 isdissolved in 50 ml. of ry chloroform, the solution is cooled,

and a saturated solution of 4.64 g. of maleic acid in dry acetone isadded dropwise. The precipitated solid is ill tered and recrystallizedfrom dry acetone to give the 2,2-

diethylbutyric acid ester of10-[3-(2-hydroxyethyl)piperazinepropyl]-Z-trifluoromethylphenothiazine,salt with two moles of nialeic acid, having a melting point of about167- Example 5 .'Stezzric acid ester of 1 0- {3- Z-hydroxyethyl pipemzirzo pro pyl -2 -tri ltzor0r/letlzyl phcnotlliaziite Following theprocedure set forth in Eample 3, but substituting 57.5 g. of stearoylchloride for 2,2-diethylbutyroyl chloride yields the stearic acid esterof lO-[3-(2-1ydroxyethyl) piperazinopropyl] 2-triiluoromethylphenothiazine, first as a pale yellow oil which later crystallizesspontaneously to a solid, having a melting point of about 33-34 C.Example 6.Stearic acid ester of 10-[3-(2-hydr0xetlzyl)-piperazinopropyl]-2-triflu0r0metlzyl phenothiazine, di-

hydrochloride 14.1 g. of the product of Example 5 are dissolved in 50ml. of dry chloroform, the solution is cooled, and 40 ml.

of a 1 molar solution of hydrogen chloride in anhydrous ether is added,dropwise, with stirring. The clear solution which forms is evaporatedfree of solvents and the residual oil induced to granulate. The solid isrecrystallized from anhydrous'acetone-ether to yield stearic acid esterof 10- [3 (2 hydroxyethyl)piperazinopropyl] 2 trifluoro methylphenothiazine, dihydrochloride having a melting point of about -8l C.

Example 7.I0-undecencic acid ester 010-[3-(2-hydroxyetlzyl)pipemzinopropyl] Z-trifluoromethylphen0-tltiaziite Following the procedure set forth in Example 3 butsubstituting 41.5 g. of lO-undecenoyl chloride for 2,2-diethylbutyroylchloride yields the lil-undecenoic acid ester of it) [3 (2hydroxyethyl)piperazine propylJ-Z-triiluoroniethylphenothiazine, as apale yellow oil. Treatment of 12.4 g. of this material according to theprocedure set forth in Example 6 yields the dihydrochloride salt of thelil-undecenoic acid ester of ll)-[3-(2-hydroxyethyl(piperazinopropyl] 2trifluoromethylphenothiazine, having an MP. of about 153155 C.

Example 8.Decaiz0ic acid ester 0 1G-[3-(2-hydr0xyethylpiper-czinopropyl] -2-triflu0r0methylphenothiazine Following theprocedure set forth in Example 3, but substituting 39.3 g. or" decanoylchloride for 2,2-diethylbutyroyl chloride, there is obtained thedecanoic acid ester of i0 [3(Z-hynoxyethyl)piperazincpropyl]-2-trifiuoro ethylphenothiazine, as apale yellow oil. Treatment of .l g. of this material according to theprocedures set orth Example 6 yields the dihydrochloride salt of 10-ecanoic acid ester of 1Q-[3-(Z-hydroxyethyl)piperazino- Iopyl]-Z-trifiuoromethylphenothiazine, having an MP. of about l75l76 C.

Example 9.10-[S-(Z-chloroetlzyl) piperazimpmpyl}2-trifiu0r0methylphenothiazine To 21.9 g. ofl0-[3-(hydroxyethyl)piperazinopropyl]- Z-trifiuoromethylphenothiazine in250 ml. of dry benzei e is added 7.1 g. of thionyl chloride. The mixtureis kept overnight, heated for 3 hours under reflux, cooled and treatedwith an excess of ethereal hydrogen chloride. The

recipitated solid is filtered and recrystallized from absoluteethanol-anhydrous ether to give 18.4 g. of lO-[S-(Z-chloroethyl)piperazinopropyl] 2 trifluorornethylphenothiazine as thedihydrochloride, MP. 224225 (dec.).

Following the procedure of *Example 9, but substituting an equivalentamount of thionyl bromide for thionyl chloride, ields10-[3-(Z-bromoethyl)piperazinopropyl}- Z-triliuoroinethylphenothiazine.

Similarly, following the procedure of Example 9, but substituting anequivalent amount of 10-[3-(2-hydroxyethoxyethyl)piperazinopropyl] 2trifluorornethylphenathiazine for10-[3-(Z-hydroxyethyl)piperazinopropyl] 2- trifluoromethylphenothiazine,yields 10 [3 (2 chloroethoxyethyl)piperazinopropyl] 2trifluoromethylphenothiazine.

Example 10.2,6-dimethyl-p-anisic acid ester 0 10-[3-(2-hydroxyethyl)piperazinopropyl] 2 trifluoromethylphenothz'azine To 2.7 g.of potassium 2,6-dirnethyl-p-anisoate in 25 ml. ofN,N-dimethylforinarnide is added 4.38 g. of 10-[3-(2-chloroethyl)piperazinopropyl] 2 trifiuoroniethylphenothiazine, themixture is stirred and heated for 5 hours at cooled, diluted with waterand. the pH adjusted to 10 with 10% aqueous sodium hydroxide solution.The mixture is extracted with ether and the ether extracts are dried andconcentrated to yield the 2,6-dimethyl-p-anisic acid ester of 10- [3 (2hydroxyethyl) piperazinopropyl]-2-tritluoromethylphenothiazine. Thisproduct in 50 ml. of anhydrous other is then reacted with 1.5 g. ofmaleic acid in 10 ml. of dry acetone, and the resultant precipitatedproduct is filtered to yield the di- M he n maleic acid salt of2,6-dimethyl-p-anisic acid ester of10-[3-(Z-hydroxyethyl)piperazinopropyl] 2 trifluoromethylphenothiazine,having a M.P. of about 160-161 C. Following the procedure set forth inExample 10, but substituting an equivalent amount of [3 (2chloroethoxyethyl)piperazinopropyl] 2 trifiuoromethylphenothiazine for10 [3 (2 chloroethyl)piperazinopropyl] 2 trifluoromethylphenothiazine,yields the 2,6- dimethyl-p-anisic acid ester of10-[3-(2-hydroxyethoxyethyl) piperazinopropyl]2-trifiuoromethylphenothiazine. Similarly, following the procedure setforth in Example 10, but substituting equivalent amounts of sodiumheptanoate; potassium naphthoate; potassium benzilate, sodiumheptynoate; potassium-Z-heptenoate; sodium S-carbomethoxy octanoate;potassium 2,6 dimethylbenzoate; sodium 2,6-dichlorobenzoate; potassiumo-bromobenzoate; and potassium o chlorobenzoate for potassium2,6-dimethyl-p-anisoate, yields respectively, the heptanoic acid;naphthoic acid; benzilic acid, heptynoic acid; heptenoic acid;S-carbomethoxyoctanoic acid; 2,6-dimethylbenz0ic acid;2,6-dichlorobenzoic acid; o-bromobenzoic acid; and o-chlorobenzoic acidesters of l0-[3-(2-hydroxyethyl) piperazinopropyl] 2trifiuoromethylphenothiazine.

Example 1 1 .I 0- [3- (Z-Izydroxyethyl pi peltlzinoprOPyl 1Z-triflaoromethylphenothiazine, ester with hepttmoic acid A mixture of3.93 g. of l0-[3-(1-piperazinyl)propyl]-2-(trifiuoromethyl)phenothiazine, 2.0 g. of 2-bromoethyl heptanoate,(ffi-bromoethyl heptanoate is readily prepared by the reaction ofheptanoyl chloride with 2-bromoethanol), 25 ml. of anhydrous toluene, 10mg. of copper powder, 10 mg. of potassium iodide and 1.38 g. ofanhydrous potassium carbonate is stirred and refluxed under nitrogen forhours. The mixture is filtered. and the filtrate concentrated to drynessto give 10-[3-(2-hydroxyethyl)piperazinopropyl] 2trifluoromethylphenothiazine, ester with heptanoic acid, as a viscouspale yellow oil.

Similarly, following the procedure set forth in Example 11, butsubstituting 2-bromoethoxyethyl heptanoate (obtained by the reaction ofheptanoyl chloride with Z-bromoethoxyethanol) for 2-bromoethylheptanoate, there is obtained 10-[3 (2hydroxyethoxyethyl)piperazinopropyl} 2-trifiuoromethylphenothiazine,ester with heptanoic acid.

Similarly, following the procedure set forth in Example 11 butsubstituting equivalent amounts of Z-bromoethyl heptynoate;2-bromoethanolbenzoate; 2-brornoethyl heptenoate 2-bromoethyl 8carbomethoxyoctanoate for 2- bromoethyl heptanoate, yields respectivelythe heptynoic acid; benzoic acid; heptenoic acid; and8-carbomethoxyoctanoate acid, esters of10-[3-(2-hydroxyethyl)piperazinopropyl] -2-trifluoromethyl.

Example 12.8-carb0meth0xy0ctanoic acid ester of 10-[3-(2-hydroxyethyl)piperazinopropyl] 2 tl'ifluolomethylplzenothiazineFollowing the procedure set forth in Example 3, but substituting 42 g.of 8-carbomethoxy octanoyl chloride for the 2,2-diethylbutyroylchloride, there is obtained the 8- carbomethoxy octanoic acid ester of10-[3-(2-hydroxyethyl)piperazinopropyl] 2 trifluoromethylphenothiazine,as a pale yellow oil. Treatment of 12.4 g. of this product in accordancewith the procedure set forth in Example 3 yields the dimaleic salt of8-carbomethoxy octanoic acid ester of10-[3-(2-hydroxyethyl)piperazinopropyl] 2 trifiuoromethylphenothiazine,having a M.P. of about 157l58 C. (dec.).

Similarly, following the procedure of Example 9 but substitutingequivalent amount of 10 carbomethoxydecanoyl chloride and1l-carbomethoxyundecanoyl chloride, for 8-carbomethoxy-octanoyl chloridethe respective l0 carbomethoxydecanoic acid; and 11carbomethoxyundecanoic acid esters of l0-[3 (2 hydroxyethyhpiperazinopropyl]-2-trifiuoromethylphenothiazine are obtained.

Example 13.-Preparati0n of 11 rarbomethowundecylenic acid (a) A mixtureof 68.4 g. of dodecylenedioic acid, 500 ml. of methanol and 10 ml. ofconcentrated sulfuric acid is heated under reflux for six hours and thenconcentrated from the steam bath. The residual oil is cooled in ice,diluted with 250 g. of ice and extracted with ether. The ether extractsare washed and saturated aqueous sodium chloride solution, dried,concentrated and the residue distilled to give dimethyldodecylenedioate.

(b) To 25.6 g. of the product from (a) in 250 ml. of methanol is added,dropwise and with stirring, a solution of 6.6 g. of potassiumhydroxidein ml. of methanol, at room temperature. Subsequently, themixture is stirred and refluxed for one hour and then concentrated fromthe steam bath. The residue is cooled, dissolved in 100 ml. of ice waterand a slight excess of 10% aqueous hydrochloric acid added. Theprecipitated solid is filtered to give 11-carbomethoxyundecylenic acid.

In similar fashion, but starting with dodecynedioic acid, there isobtained 11-carbomethoxyundecylynic acid.

Example ]4.--10-[3-(Z-hydroxyethyl)piperazinopropyl]-Z-trzfluoromethylphenotlziazinc, ester with stearic acid A mixture of4.37 g. of 10-[3-(2-hydroxyethyl)piperazinopropyl] 2-trifluoromethylphenothiazine, 2.98 g. of methyl stearate and 10 mg. ofanhydrous sodium methoxide are heated by means of an oil bath maintainedat 100. The methanol distills as it is formed and the reaction iscomplete in about 3 hours. The cooled mixture is dissolved in 100 ml. ofether and the ether solution is washed with three 10 ml. portions ofcold water. The dried ether solution is concentrated to dryness to give10-[3 (2 hydroxyethyl)piperazinopropyl] 2 trifiuoromethylphenothiazine,ester with stearic acid, as a pale yellow oil. When a seed crystal ofthe material obtained in Example 6 is added, this product alsocrystallizes to a solid, M.P. about 33-34" C.

Similarly, following the procedure set forth in Example 14 butsubstituting equivalent amounts of methyl benzoate; methyl heptynoate;methyl heptenoate and methyl heptanoate for methyl stearate, there areobtained respectively the benzoic acid; heptynoic acid; heptenoic acidand heptanoic acid esters ofl0-[3-(2-hydroxyethyl)piperazinopropyl]-2-trifiuoromethylphenothiazine.

Example 15.10-[3-(2-hydr0xyethyl)piperazinopropyl]-Z-trifluoromethylphenothiazine, ester with benzilic acid (a) To 4.37 g.of10-[3-(Z-hydroxyethyl)piperazinopropyl]-2-trifluoromethylphenothiazinein 50 ml. of chloroform is added 2.65 g. of2,2-bis-phenyl-Z-chloroacetyl chloride in 25 ml. of chloroform. Themixture is refluxed for 24 hours and concentrated to givel0-[3-(2-hydroxyethyl)piperazinopropyl] 2 trifluoromethylphenothiazine,ester with 2,2-bis-phenyl-2-chloroacetic acid as a pale yellow oil.

(b) The product from (a) in'50 ml. of ether, 250 ml. of water and 0.84g. of sodium bicarbonate are stirred and heated at 35 for one hour. Theether layer is separated, dried and concentrated to givel0-[3-(2-hydroxyethyl)piperazinopropyl] -2 trifiuoromethylphenothiazine,ester with benzilic acid.

Similarly, following the procedures set forth in Example 15, butsubstituting 10-[3-(2-hydroxyethoxyethyl)-piperazinopropyl]-2-trifiuoromethylphenothiazine for 10[3-(Z-hydroxyethyl)piperazinopropyl] 2 trifiuoromethylphenothiazineyields 10 [3-(2 hydroxycthoxyethyl)- piperazinopropyl] 2trifluoromethylphen'othiazine, ester with benzilic acid.

Example 16.Parenteral formulation A 50 g. of the heptanoie acid ester of10-[3-(2-hydroxyethyl)piperazinopropyl] 2 trifluoromethylphenothiazineobtained as in Example 2 is dissolved in 1000 ml. of

9 sesame oil, U.S.P. The solution is sterile filtered and packagedasceptically for parenteral administration.

Example 1 7.Parenteral formulation B A suspension of 56 g. of micronizedheptanoic acid ester of -[3-(Z-hydroxyethyl)piperazinopropyl]-2trifiuoromethylphenothiazine, prepared as in Example 2, 0.36 g. oflecithin, N.F., 0.18 g. of Tween 80 and 1.68 g. of aluminum monostearate(purified), diluted to 1000 ml. with sesame oil is prepared understerile conditions and packaged aseptically for parenteraladministration.

Example 18.Parenteral formulation C A solution of g. of the heptanoicacid ester of 10-[3-(2 hydroxyethyl)piperazinopropyl] 2trifluoromethylphenothiazine, 1.5 g. aluminum monostearate (purified)diluted to 1000 ml. with sesame oil, U.S.P., is sterile filtered andpackaged aseptically for parenteral administrtaion.

This invention may be variously otherwise embodied within the scope ofthe appended claims.

What is claimed is:

1. A pharmaceutical composition for parenteral administration in thetreatment of mental disorders, said composition characterized byprolonged duration of activity which comprises, in combination (I) aphysiologically ac tive compound of the formula wherein r is a positiveinteger of from one to two; X is selected from the group consisting ofchloro and trifluoromethyl; and Y is selected from the group consistingof higher alkyl of from six to fourteen carbon atoms, higher alkenyl offrom six to fourteen carbon atoms, higher alkynyl of from six tofourteen carbon atoms, tolyl, dimethyl benzyl, anisyl, and

wherein r is a positive integer of from one to two; X is selected fromthe group consisting of chloro and trifluoromethyl; and Y is selectedfrom the group consisting of higher alkyl of from six to fourteen carbonatoms, higher alkenyl of from six to fourteen carbon atoms, higheralkynyl of from six to fourteen carbon atoms, tolyl, dimethyl benzyl,anisyl, and

0 (011;) n ii- O CH3 wherein n is a positive integer of from seven totwelve; and (II) a stable, non-toxic, pharmaoeutically acceptable,non-aqueous liquid carrier selected from the group consisting ofvegetable oils, synthetic glycerol esters of long chain fatty acids andmixtures thereof; wherein the concentration of the said physiologicallyactive compound is from about 20 mg./ml. to about 3*00 mg./ml.

3. A pharmaceutical composition for parenteral administration in thetreatment of mental disorders, said composition characterized byprolonged duration of activity which comprises, in combination (I) thehigher alkanoic acid ester of from seven to fifteen carbon atoms of10-[3- (2 hydroxyethyl)piperazinopropyl] 2 trifiuoromethylphenothiazineand (If) a stable, non-toxic, pharmaceuticaily acceptable, non-aqueousliquid carrier selected from the group consisting of vegetable oils,synthetic glycerol esters of long chain fatty acids and mixturesthereof.

t. A pharmaceutical composition for parenteral administration in thetreatment of mental disorders, said composition characterized byprolonged duration of activity which comprises, in combination (I) thehigher alkanoic acid ester of from seven to fifteen carbon atoms of10-[3- (2 hydroxyethyl)piperazinopropyl] 2 trifluoromethylphenothiazineand (H) a stable, non-toxic, pharmaceutically acceptable, non-aqueousliquid carrier selected from the group consisting of vegetable oils,synthetic glycerol esters of long chain fatty acids and mixturesthereof; wherein the concentration of the said higher alkanoic acidester is from about 20 mg./ml. to about 300 rug/ml.

5. A pharmaceutical composition for parenteral administration in thetreatment of mental disorders, said composition characterized byprolonged duration of activity which comprises, in combination (I) thedecanoic acid ester of 10-[3-(Z-hydroxyethyl)piperazinopropyl]-2-trifluoromethylphenothiazine and (H) a stable, non-toxic, pharmaceuticallyacceptable, non-aqueous liquid carrier selected from the groupconsisting of vegetable oils, synthetic glycerol esters of long chainfatty acids and mixtures thereof; wherein the concentration of the saiddecanoie acid ester of10-[3-(Z-hydroxyethyl)piperazinopropyl]-2-trifluoromethylphenothiazineis from about 20 mg/ml. to about 300 mg./ml.

, 6. A pharmaceutical composition for parenteral administration in thetreatment of mental disorders, said composition characterized byprolonged duration of activity which comprises, in combination (I) thedecanoic acid ester of 19- 3- (Z-hydroxyethyl) piperazinopropyl]-2-trifluonomethylphenothiazine and (II) a stable, non-toxic,pharmaceutically acceptable, non-aqueous liquid carrier selected fromthe group consisting of vegetable oils, synthetic glycerol esters oflong chain fatty acids and mixtures thereof.

'7. The method of treating patients for mental disorders which comprisesparenterally administering once every two to three weeks to the saidpatients a small but effective amount of a composition comprising, incombination (I) a physiologically active compound of the formula whereinr is a positive integer of from one to two; X is selected from the groupconsisting of chloro and trifluoromethyl; and Y is selected from thegroup consisting of higher allryl of from six to fourteen carbon atoms,higher alkenyl of from six to fourteen carbon atoms, higher alkynyl offrom six to fourteen carbon atoms, tolyl, dimethyl benzyl, anisyl and(CH2).. io-GH3 wherein n is a positive integer of from seven to twelve;and (II) a stable, non-toxic, pharmaceutically acceptable, non-aqueousliquid carrier selected from the group consisting of vegetable oils,synthetic glycerol esters of long chain fatty acids and mixturesthereof.

- l l 8. The method of treating patients for mental disorders whichcomprises parenterally administering once every two to three Weeks tothe said patients about one milliliter of a composition comprising, incombination (I) a physiologically active compound of the formula whereinr is a positive integer of from one to two; X is 0 (CH2),,( J-O-OHwherein n is a'positive integer of from seven to twelve; and (II) astable, non-toxic, pharmaceutically acceptable,

non-aqueous liquid carrier selected from the group c0nsisting ofvegetable oils, synthetic glycerol esters of long chain fatty acids andmixtures thereof; wherein the concentration of the said physiologicallyactive compound is from about 20 mg./ml. to about 300 mg./ml. 9. Amethod of treating patients for mental disorders which comprisesparenterally administering once every two to three weeks, to the saidpatients about one milliliter of a composition comprising, incombination, the heptanoic acid ester of-[3-(Z-hydroxyethyl)piperazinopropyl]-2-trifiuoromethylphenothiazine anda stable, nontoxic, pharmaceutically acceptable non-aqueous liquidcarrier selected. from the group consisting of vegetable oils, syntheticglycerol esters of long chain fatty acids and mixtures thereof; whereinthe concentration of the said heptanoic acid ester of10-[3-(2-l1ydroxyethyl)piperazinopropyl]-2-trifluoromethylphenothiazineis from aboutZO. mg./ml. to about 300 mtg/ml.

10. A method of treating patients for mental disorders which comprisesparenterally administering once every 4 methylphenothiazine and astable, non-toxic, pharmaceuti-cally acceptable non-aqueous liquidcarrier selected from the group consisting of vegetable oils, syntheticglycerol esters of long chain 'fatty acids and mixtures thereof; whereinthe concentration of the said higher .alkanoic acid ester of from sevento fifteen carbon atoms of 10-[3-(2- hydroxyethyl) piperazinopropyl] -2trifiuoromethylphenothiazine is from about 20 mgJml. to about 300 mg/ml.

11. A method of treating patients for mental disorders which comprisesparenterally administering once every two to three weeks, to the saidpatients about one milliliter of a compositioncomprising, incombination, the decanoic acid ester of10-[3-(2-hydroxyethyl)piperazinopropyl]-2- trifiuoromethylphenothiazineand a stable non-toxic, pharmaceutically acceptable non-aqueous liquidcarrier selected from the group consisting of vegetable oils, syntheticglycerol esters of long chain fatty acids and mixtures thereof; whereinthe concentration of the said decanoic acid ester of10-[3-(241ydroxyethyl)piperazinopropyl]-2-trifluoromethylphenothiazineis from about 20 mg./rnl. to about 300 mglml.

References Cited by the Examiner UNITED STATES PATENTS 2,507,193 5/50Buckwalter l6758 2,544,272 3/51 Miller 16758 2,744,851 5/56 Halpern etal. 16758 2,892,753 6/59 Schmidt 16765 2,928,767 3/60 Gulesich 2602433,058,979 10/62 .Ullyot 260-243 3,419,032 9/64 \Varing 16758 FOREIGNPATENTS 553,467 6/57 Belgium.

568,701 7/58 Belgium.

568,837 12/58 I Belgium.

829,246 3/60 Great Britain.

845,943 8/60 Great Britain.

OTHER REFERENCES Buckwalter, I. Am. Pharm. Assoc. Sci. Ed., vol. XLVII,No. 4, page 662, September 1958.

Voss, J. of Am. Pharm. Assoc. Sci. Ed., 43, 1954, 690, Wyman Card, May1955.

JULIAN S. LEVITT, Primary Examiner.

JOHN D. RANDOLPH, Examiner.

1. A PHARMACEUTICAL COMPOSITION FOR PARENTERAL ADMINISTRATION IN THETREATMENT OF MENTAL DISORDERS, SAID COMPOSITION CHARACTERIZED BYPROLONGED DURATION OF ACTIVITY WHICH COMPRISES, IN COMBINATION (1) APHYSIOLOGICALLY ACTIVE COMPOUND OF THE FORMULA